Nonsyndromic Cleft Lip/Palate (NSCLP) is a complex genetic disorder caused by both genetic and environmental factors. While traditional approaches have achieved some success in uncovering NSCLP's genetic etiology, the majority of NSCLP genetic risk remains unknown. The nature of complex genetic architectures, wherein many loci contribute modest effects at the population level, entails that genome-wide association studies are often underpowered for detecting most risk loci, particularly after correction for multiple testing. Hence, researchers in NSCLP frequently rely on candidate gene approaches to increase statistical power. Candidate gene strategies, however, are limited by our prior knowledge of the relevant biological pathways. In effect, we often end up looking under the proverbial lamp post for mutations in genes that are related to those already identified. Here, we propose a fundamentally different approach. By intelligently leveraging the detection of spontaneously arising mutations, via three independent strategies, we can extend our candidate gene search outside known and/or suspected genetic pathways. We propose to conduct a multi- pronged genome-wide screening strategy to detect disruptive mutations in NSCLP cases. The first component of our screen targets a rarely studied subtype of structural variation. While the involvement of CNVs in the etiology of several Mendelian and complex genetic disorders is now widely acknowledged, the contribution of transposable element (TE) insertions to genetic disease has received scarce attention. Although much of the TE content in the genome consists of dormant copies that are incapable of further proliferation, several lineages of type I retrotransposons (Alu, L1, SVA, and ERVs) remain active within humans. Thus far, over 20 distinct genetic disorders have been identified in which TE insertions have resulted in disease alleles. In laboratory settings, artificially induced TE insertions have routinely been employed in model organisms to generate knock-out mutations for the purpose of establishing gene-phenotype relationships. The advent of highly parallel 2nd Generation Sequencing allows this same conceptual strategy to be implemented in humans. By screening for potentially disruptive TE insertions in individuals with known disease phenotypes, it is possible to generate an unbiased set of candidate regions for further genetic interrogation. We will combine this novel TE screening approach with a triad aCGH screening strategy, wherein we cross-hybridize NSCLP cases to each of their parents, allowing for the immediate identification of de novo copy number events in sporadic NSCLP cases. Finally, to round out our screening strategy with a methodology targeting inherited NSCLP risk factors, we will conduct exome sequencing within multiplex NSCLP families. Together, these complementary approaches can greatly enhance our ability to rapidly identify candidate genes/region for further scrutiny. We will evaluate these genes/regions via a targeted genotyping approach and conduct further molecular characterization, including zebrafish modeling, of the most promising loci.